Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis–van Creveld syndrome patients

Abstract

Ellis-van Creveld syndrome (EvC) is caused by mutations in EVC and EVC2, genes in a divergent orientation separated by only 2.6 kb. We systematically sought mutations in both genes in a panel of 65 affected individuals to assess the proportion of cases resulting from mutations in each gene. We PCR amplified and sequenced the coding exons of both genes. We investigated mutations that could affect splicing by in vitro splicing assays and cDNA analysis. We have identified EVC mutations in 20 cases (31%); in all of these we have detected the mutation on each allele. We have identified EVC2 mutations in 25 cases (38%); in 22 of these we have isolated a mutation on each allele. The majority of the mutations introduce a premature termination codon. We sequenced the region between the two genes in 10 of the 20 cases in which we had not identified a mutation in either gene, revealing only one SNP that was not a common polymorphism. As we have not identified mutations in either gene in 20 cases (31%) it is possible that there is further genetic heterogeneity.

Epidemiology and Etiology of Congenital Heart Diseases

“…Mutation of this gene has been implicated in both Ellis-van Creveld syndrome and Weyers acrodental dysostosis, the disease locus mapped to chromosome 4p16 (Polymeropoulos et al, 1996). Ellis-van Creveld syndrome is an autosomal recessive disorder characterized by chondrodysplasia and CHD, typically a common atrium of the atrioventricular septal defect type or secundum type atrial septal defects (Ali et al, 2010;Hills et al, 2011;Tompson et al, 2007 (Micale et al, 2010;Rodriguez-Revenga et al, 2005;Arrington et al, 2006).  FBN1, fibrillin 1; This gene encodes a member of the fibrillin family.…”

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

“…EVC and EVC2 are adjacent genes identified in the recessive skeletal dysplasia Ellis-van Creveld syndrome (EvC; MIM: 225500), and loss-of-function mutation in either gene leads to the same condition [31][32][33][34]. Recent studies indicate that Evc promotes chondrocyte proliferation, hypertrophy and the differentiation of osteoblasts in the perichondrium, and localizes to the primary cilia of osteoblasts to mediate Hh signaling in the osteoblast lineage [35].…”

Ellis—van Creveld Syndrome with Sagittal Craniosynostosis

“…5,6 No known mutation has been identified in the other one-third. 7 In this case, the patient and his older sister both carried a clinical diagnosis of the EVC, without mutation in either EVC1 or EVC2.…”